Obsessive-Compulsive DisorderNCT05467683
CO2 Reactivity as a Biomarker of Non-Response to Exposure-Based Therapy
A study testing Exposure-Based Therapy in people with Obsessive-Compulsive Disorder and Post Traumatic Stress Disorder, run by Jasper A. Smits at 2 sites in United States.
Trial summary
Anxiety-, obsessive-compulsive and trauma- and stressor-related disorders reflect a significant public health problem. This study is designed to evaluate the predictive power of a novel biomarker based on a CO2 challenge, thus addressing the central question "can this easy-to-administer assay aid clinicians in… Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Obsessive-Compulsive Disorder, Post Traumatic Stress Disorder, Generalized Anxiety Disorder
- What is being tested?
- Exposure-Based Therapy
- Type of treatment
- Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 600 participants
- Where
- 2 sitesUnited States
- Study dates
- 2 Nov 2022to 28 Feb 2027
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- A primary DSM-5 diagnosis of panic disorder (with or without an agoraphobia diagnosis), social anxiety disorder, generalized anxiety disorder, obsessive-compulsive disorder, or post-traumatic stress disorder as assessed by the Structured Clinical Interview for the DSM-5 (SCID-5)
- A score of 8 or greater on the Overall Anxiety Severity and Impairment Scale (OASIS)
- Ages 18 to 70
- Willingness and ability to provide informed consent and comply with the requirements of the study protocol.
- Proficiency in English (because assessment instruments have only been validated in English)
Who cannot join
- A lifetime history of bipolar or psychotic disorders, substance use disorders (other than nicotine) or eating disorder in the past 6 months; serious cognitive impairment.
- Active suicidal ideation with at least some intent to act with or without specific plan (a rating of 4 for suicidal ideation on the Columbia-Suicide Severity Rating Scale) or suicidal behaviors (actual attempt, interrupted attempt, aborted or self-interrupted attempt, or preparatory acts or behavior) within the past 6 months.
- Medical conditions contraindicating CO2 inhalation or hyperventilation challenge (e.g., cardiac arrhythmia, cardiac failure, asthma, lung fibrosis, high blood pressure, epilepsy, or stroke).
- Pregnancy or lactation
- Ongoing psychotherapy directed toward the primary disorder.
- Pharmacological treatment started within 8 weeks prior to the screen (patients "stable" on their medication regimen will be included and their medication status will be included as a variable in the model)
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States2 sites, 2 recruiting
- Recruiting
The University of Texas at Austin
Austin, Texas, 78712
Jasper Smits, Ph.D., 512-475-8095, smits@utexas.edu
- Recruiting
Boston University
Boston, Massachusetts, 02215
Michael Otto, Ph.D., 617-353-9610, mwotto@bu.edu
About this study
Official title: Carbon Dioxide (CO2) Reactivity as a Biomarker of Non-Response to Exposure-Based Therapy
Anxiety-, obsessive-compulsive and trauma- and stressor-related disorders reflect a significant public health problem. This study is designed to evaluate the predictive power of a novel biomarker based on a CO2 challenge, thus addressing the central question "can this easy-to-administer assay aid clinicians in deciding whether or not to initiate exposure-based therapy?"
Read the detailed description
Exposure-based therapy is an effective first-line treatment for anxiety-, obsessive-compulsive and trauma- and stressor-related disorders. However, many patients fail to respond or achieve remission with exposure-based therapy, resulting in prolonged suffering, loss of productivity, and poorly used resources. Making available a biomarker assay that can aid clinicians and patients in treatment selection has the potential to have considerable public health impact.
Basic research on fear extinction--a core mechanism of action of exposure-based therapy--may inform the development of a biomarker for the selection (yes/no) of exposure-based therapy. Growing evidence links orexin system activity to deficits in fear extinction. Our group has demonstrated that reactivity to CO2 challenge, which is a safe, affordable and easy-to-implement procedure, can serve as a proxy for orexin system activity and predicts fear extinction deficits in rodents.
Building upon this basic research, the goal for the proposed study is to validate CO2 reactivity as a biomarker of exposure-based therapy non-response. To this end, we will assess CO2 reactivity in 600 adults meeting for one or more fear- or anxiety-related disorders prior to providing open, state-of-the art, transdiagnostic exposure-based therapy. By incorporating CO2 reactivity into a multivariable model predicting treatment non-response that also includes reactivity to hyperventilation as well as a number of related and theoretically-relevant prognostic variables, we will establish the mechanistic specificity and the additive predictive value of the putative biomarker. By developing models independently within two study sites and predicting the other site's data, we will validate that the results are likely to generalize to future clinical samples.
The proposed study represents a necessary stage in translating basic research to strategies for treatment selection. The investigation addresses an important public health issue by testing an accessible clinical assessment strategy--informed by basic research--that may lead to a more effective treatment selection (personalized medicine) for patients with anxiety- and fear-related disorders and enhance our understanding of the mechanisms governing exposure-based therapy.
- Conditions
- Obsessive-Compulsive Disorder, Post Traumatic Stress Disorder, Generalized Anxiety Disorder, Social Anxiety Disorder, Panic Disorder
- Being tested
- Exposure-Based Therapy
- Medical subject headings
- Obsessive-Compulsive Disorder, Stress Disorders, Post-Traumatic, Generalized Anxiety Disorder, Phobia, Social, Panic Disorder
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Exposure-Based TherapyBehavioural
Treatment will consist of 12 one-hour sessions, delivered over the course of 12 weeks. EBT will be delivered by trained and experienced license-eligible clinicians. The study clinician will develop a personalized assessment and treatment plan for each patient. Consistent with contemporary models of EBT, exposure practice aims to help patients reestablish a sense of safety around feared cues. Hence, exposure exercises are planned to ensure violation of threat expectancies. That is, exposure practice is deemed appropriate and effective if it allows the patient to learn that what they feared would happen does not happen. Practice will occur across relevant contexts both within and outside the session (i.e., homework) and clinicians will guide patients in processing practice to facilitate the consolidation of safety learning. To achieve these ends, study clinicians will use the manual "Personalized Exposure Therapy: A Person-Centered Transdiagnostic Approach".
| Study group | Role | What they receive |
|---|---|---|
| Open Exposure-Based Therapy (EBT) | Other | All participants will receive a well-established psychological treatment. Receives: Behavioral: Exposure-Based Therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Non-response to exposure-based therapy
Participants will be classified as non-responders if their Clinical Global Impression - Global Improvement (CGI-I) score is 3 or above OR if their Overall Anxiety Severity and Impairment Scale (OASIS) score has not improved by at least 4 points.
Measured: Week 13 (post-treatment)
Secondary outcomes (7)
Clinical Global Impression - Severity of Illness (CGI-S)
A 7 point widely used clinician rating scale for indexing the how mentally ill a patient is at the time using a 7 point scale ranging from 1(normal, not at all ill); 2 (borderline mentally ill); 3 (mildly ill); 4 (moderately ill); 5 (markedly ill); 6 (severely ill); 7(among the most extremely ill patients).
Measured: Weekly for 14 weeks + follow-up after 24 weeks
Overall Anxiety Severity and Impairment Scale (OASIS)
The OASIS is a self-report rating scale that comprises five items to assess the frequency and severity of anxiety, avoidance, work/school/home interference, and social interference due to anxiety. Participants select among five different response options for each item, which are coded 0-4 and are summed to obtain a total score (0-20).
Measured: Weekly for 14 weeks + follow-up after 24 weeks
GAD-7
For participants with generalized anxiety disorder (GAD) as their primary DSM-V diagnosis, intended to assess the severity of participant symptoms. Ranged from 0 to 21, with higher scores indicating more severe distress and impairment.
Measured: Weekly for 14 weeks + follow-up after 24 weeks
Panic Disorder Severity Scale (PDSS)
For participants with panic disorder (PD) as their primary DSM-V diagnosis, intended to assess the severity of participant symptoms. Ranged from 0 to 28, with higher scores indicating more severe distress and impairment.
Measured: Weekly for 14 weeks + follow-up after 24 weeks
Social Phobia Inventory (SPIN)
For participants with social anxiety disorder (SAD) as their primary DSM-V diagnosis, intended to assess the severity of participant symptoms. Ranged from 0 to 68, with higher scores indicating more severe distress and impairment.
Measured: Weekly for 14 weeks + follow-up after 24 weeks
Dimensional Obsessive-Compulsive Scale (DOCS)
For participants with obsessive compulsive disorder (OCD) as their primary DSM-V diagnosis, intended to assess the severity of participant symptoms. Ranged from 0 to 80, with higher scores indicating more severe distress and impairment.
Measured: Weekly for 14 weeks + follow-up after 24 weeks
PTSD Checklist for DSM-5 (PCL-5)
For participants with post-traumatic stress disorder (PTSD) as their primary DSM-V diagnosis, intended to assess the severity of participant symptoms. Ranged from 0 to 80, with higher scores indicating more severe distress and impairment.
Measured: Weekly for 14 weeks + follow-up after 24 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jul 2022
- Study start2 Nov 2022
- Primary completion1 Dec 2026 (estimated)
- Study completion28 Feb 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Obsessive-Compulsive DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 600 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Jasper A. Smits
- Sponsor type
- University, hospital or other
- Collaborators
- Boston University, National Institute of Mental Health (NIMH)
- Responsible party
- Sponsor-investigator, Jasper A. Smits, University of Texas at Austin
- Investigators
- Jasper Smits, Ph.D., Principal investigator, The University of Texas at AustinMichael Otto, Ph.D., Principal investigator, Boston University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05467683
- Sponsor's protocol ID
- STUDY00001631
- Other IDs
- 1R01MH125951-01A1, 1R01MH125949-01A1
- Status last verified
- Jun 2026
- First submitted
- 27 Jun 2022
- Last updated
- 10 Jun 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: In line with National Institute of Mental Health (NIMH) guidance, we will share de-identified data derived from this study via the National Data Archive (NDA), along with supporting documentation to enable efficient and appropriate use of the data. Data sharing is now a requirement for all NIMH-funded awards (NOT-MH-14-015). Consistent with the National Database for Clinical Trials related to Mental Illness (NDCT) guidelines, we will share data in a two-tiered approach. The first tier involves semi-annual uploading of descriptive and raw data while the study is ongoing, including data from standard assessments, standard clinical measures, demographic data, and raw behavioral data. The second tier includes analyzed data that result from publications. We will ensure that submitted data will conform to relevant data and terminology standards. Throughout our resource sharing plan, we will comply with NDCT guidelines.
Publications
Smits JAJ, Monfils MH, Otto MW, Telch MJ, Shumake J, Feinstein JS, Khalsa SS, Cobb AR, Parsons EM, Long LJ, McSpadden B, Johnson D, Greenberg A; Exposure Therapy Consortium. CO2 reactivity as a biomarker of exposure-based therapy non-response: study protocol. BMC Psychiatry. 2022 Dec 27;22(1):831. doi: 10.1186/s12888-022-04478-x.
PubMed 36575425
Study at a glance
From the registry record, last updated by the sponsor on 10 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Carbon Dioxide (CO2) Reactivity as a Biomarker of Non-Response to Exposure-Based Therapy
- ClinicalTrials.gov ID
- NCT05467683
- Acronym / sponsor ID
- STUDY00001631
- Conditions
- Obsessive-Compulsive Disorder, Post Traumatic Stress Disorder, Generalized Anxiety Disorder, Social Anxiety Disorder, Panic Disorder
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 600 participants (estimated)
- Lead sponsor
- Jasper A. SmitsUniversity, hospital or other
- Collaborators
- Boston University, National Institute of Mental Health (NIMH)
- Study start
- 2 Nov 2022 (actual)
- Primary completion
- 1 Dec 2026 (estimated)
- Study completion
- 28 Feb 2027 (estimated)
- First posted
- 20 Jul 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Anxiety-, obsessive-compulsive and trauma- and stressor-related disorders reflect a significant public health problem. This study is designed to evaluate the predictive power of a novel biomarker based on a CO2 challenge, thus addressing the central question "can this easy-to-administer assay aid clinicians in deciding whether or not to initiate exposure-based therapy?"
Detailed description
Exposure-based therapy is an effective first-line treatment for anxiety-, obsessive-compulsive and trauma- and stressor-related disorders. However, many patients fail to respond or achieve remission with exposure-based therapy, resulting in prolonged suffering, loss of productivity, and poorly used resources. Making available a biomarker assay that can aid clinicians and patients in treatment selection has the potential to have considerable public health impact.
Basic research on fear extinction--a core mechanism of action of exposure-based therapy--may inform the development of a biomarker for the selection (yes/no) of exposure-based therapy. Growing evidence links orexin system activity to deficits in fear extinction. Our group has demonstrated that reactivity to CO2 challenge, which is a safe, affordable and easy-to-implement procedure, can serve as a proxy for orexin system activity and predicts fear extinction deficits in rodents.
Building upon this basic research, the goal for the proposed study is to validate CO2 reactivity as a biomarker of exposure-based therapy non-response. To this end, we will assess CO2 reactivity in 600 adults meeting for one or more fear- or anxiety-related disorders prior to providing open, state-of-the art, transdiagnostic exposure-based therapy. By incorporating CO2 reactivity into a multivariable model predicting treatment non-response that also includes reactivity to hyperventilation as well as a number of related and theoretically-relevant prognostic variables, we will establish the mechanistic specificity and the additive predictive value of the putative biomarker. By developing models independently within two study sites and predicting the other site's data, we will validate that the results are likely to generalize to future clinical samples.
The proposed study represents a necessary stage in translating basic research to strategies for treatment selection. The investigation addresses an important public health issue by testing an accessible clinical assessment strategy--informed by basic research--that may lead to a more effective treatment selection (personalized medicine) for patients with anxiety- and fear-related disorders and enhance our understanding of the mechanisms governing exposure-based therapy.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Open Exposure-Based Therapy (EBT) | Other | Behavioral: Exposure-Based TherapyAll participants will receive a well-established psychological treatment. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- A primary DSM-5 diagnosis of panic disorder (with or without an agoraphobia diagnosis), social anxiety disorder, generalized anxiety disorder, obsessive-compulsive disorder, or post-traumatic stress disorder as assessed by the Structured Clinical Interview for the DSM-5 (SCID-5)
- A score of 8 or greater on the Overall Anxiety Severity and Impairment Scale (OASIS)
- Ages 18 to 70
- Willingness and ability to provide informed consent and comply with the requirements of the study protocol.
- Proficiency in English (because assessment instruments have only been validated in English)
Key exclusion criteria (6 listed)
- A lifetime history of bipolar or psychotic disorders, substance use disorders (other than nicotine) or eating disorder in the past 6 months; serious cognitive impairment.
- Active suicidal ideation with at least some intent to act with or without specific plan (a rating of 4 for suicidal ideation on the Columbia-Suicide Severity Rating Scale) or suicidal behaviors (actual attempt, interrupted attempt, aborted or self-interrupted attempt, or preparatory acts or behavior) within the past 6 months.
- Medical conditions contraindicating CO2 inhalation or hyperventilation challenge (e.g., cardiac arrhythmia, cardiac failure, asthma, lung fibrosis, high blood pressure, epilepsy, or stroke).
- Pregnancy or lactation
- Ongoing psychotherapy directed toward the primary disorder.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Exposure-Based TherapyTreatment will consist of 12 one-hour sessions, delivered over the course of 12 weeks. EBT will be delivered by trained and experienced license-eligible clinicians. The study clinician will develop a personalized assessment and treatment plan for each patient. Consistent with contemporary models of EBT, exposure practice aims to help patients reestablish a sense of safety around feared cues. Hence, exposure exercises are planned to ensure violation of threat expectancies. That is, exposure practice is deemed appropriate and effective if it allows the patient to learn that what they feared would happen does not happen. Practice will occur across relevant contexts both within and outside the session (i.e., homework) and clinicians will guide patients in processing practice to facilitate the consolidation of safety learning. To achieve these ends, study clinicians will use the manual "Personalized Exposure Therapy: A Person-Centered Transdiagnostic Approach". | Behavioural | Open Exposure-Based Therapy (EBT) |
Primary outcome
Non-response to exposure-based therapy
Time frame: Week 13 (post-treatment)
Participants will be classified as non-responders if their Clinical Global Impression - Global Improvement (CGI-I) score is 3 or above OR if their Overall Anxiety Severity and Impairment Scale (OASIS) score has not improved by at least 4 points.
7 secondary outcomes
Clinical Global Impression - Severity of Illness (CGI-S)
Time frame: Weekly for 14 weeks + follow-up after 24 weeks
Overall Anxiety Severity and Impairment Scale (OASIS)
Time frame: Weekly for 14 weeks + follow-up after 24 weeks
GAD-7
Time frame: Weekly for 14 weeks + follow-up after 24 weeks
Panic Disorder Severity Scale (PDSS)
Time frame: Weekly for 14 weeks + follow-up after 24 weeks
Social Phobia Inventory (SPIN)
Time frame: Weekly for 14 weeks + follow-up after 24 weeks
Dimensional Obsessive-Compulsive Scale (DOCS)
Time frame: Weekly for 14 weeks + follow-up after 24 weeks
PTSD Checklist for DSM-5 (PCL-5)
Time frame: Weekly for 14 weeks + follow-up after 24 weeks
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Jun 2026.
- Derived from this study: PubMed 36575425Smits JAJ, Monfils MH, Otto MW, Telch MJ, Shumake J, Feinstein JS, Khalsa SS, Cobb AR, Parsons EM, Long LJ, McSpadden B, Johnson D, Greenberg A; Exposure Therapy Consortium. CO2 reactivity as a biomarker of exposure-based therapy non-response: study protocol. BMC Psychiatry. 2022 Dec 27;22(1):831. doi: 10.1186/s12888-022-04478-x.
- Individual participant dataSharing planned: Yes. In line with National Institute of Mental Health (NIMH) guidance, we will share de-identified data derived from this study via the National Data Archive (NDA), along with supporting documentation to enable efficient and appropriate use of the data. Data sharing is now a requirement for all NIMH-funded awards (NOT-MH-14-015). Consistent with the National Database for Clinical Trials related to Mental Illness (NDCT) guidelines, we will share data in a two-tiered approach. The first tier involves semi-annual uploading of descriptive and raw data while the study is ongoing, including data from standard assessments, standard clinical measures, demographic data, and raw behavioral data. The second tier includes analyzed data that result from publications. We will ensure that submitted data will conform to relevant data and terminology standards. Throughout our resource sharing plan, we will comply with NDCT guidelines.
Related trials for Obsessive-Compulsive Disorder
Enrolling by invitation
Family Accommodation Reduction in Adult Obsessive Compulsive Disorder
Obsessive - Compulsive Disorder, Family Accommodation
Not yet recruitingObservational study
Investigation of Obsessive-Compulsive Disorder in Patients With Elbow Epicondylitis
Lateral Epicondylitis, Medial Epicondylitis
Recruiting
Precision Analytic Research Methods in OCD
Obsessive Compulsive Disorder
Recruiting
Focused Ultrasound for Behavioral Health
Depression, Anxiety
Not yet recruiting
Linear Accelerator Radiosurgical Anterior Capsulotomy With Task-based fMRI Identification of PERSonalized and PrEdictiVE Biomarkers of REsponse in Treatment-Refractory Obsessive-Compulsive Disorder (PERSEVERE Trial)
Treatment-refractory Obsessive-compulsive Disorder (trOCD)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Jasper Smits, Ph.D. principal investigator
The University of Texas at Austin
Michael Otto, Ph.D. principal investigator
Boston University
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Exposure-Based Therapy in people with Obsessive-Compulsive Disorder and Post Traumatic Stress Disorder, run by Jasper A. Smits at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 10 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Non-response to exposure-based therapy (time frame: Week 13 (post-treatment)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05467683, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jun 2026.